Project Summary Most of the 200k Americans who undergo thoracotomy each year receive opiates to reduce postoperative pain because clinicians have few non-addictive, cost-effective choices to control the severe pain patients often experience in the first two weeks after surgery. Managing pain post-thoracotomy is critical to enable patients to take deep breaths and remove (via coughing) lung secretions that otherwise significantly increase risk of pneumonia and collapsed lung, hospital re-admission and morbidity. The most severe pain associated with thoracotomy is transmitted along the intercostal nerves. But no long-term analgesic or nerve block device exists that can provide safe and effective long-term reduction of pain. While drug cocktails often temporarily reduce pain in many patients, and electrical stimulators provide partial relief (50-75% of patients at best), a universally applicable non-addictive pain treatment modality is needed. A reversible, patient-controlled, non- addictive, intercostal nerve block device would reduce suffering due to thoracotomy, broken ribs and herpes zoster. In this Phase I project, we will develop a minimally invasive thermal nerve block device that can control nerve conduction by gently warming and cooling a short nerve segment between room temperature and warm water temperature. This novel approach is based on the discovery that warm and cool temperature mechanisms of nerve block are different and additive, enabling moderate-temperature nerve block by cycling neural tissues slightly above and below body temperature. Reversible thermal nerve blocks represent a completely new approach to managing pain. Having completed work in felines and met with FDA, Aim #1 will complete the development of the minimally invasive thermal tips for ease of implantation, develop the control system to operate the device safely, and evaluate the functional performance of the system for blocking intercostal nerve pain (C-fiber) signals induced by skin pinprick in anesthetized felines and sheep. The thermal tip will cycle nerve temperatures between 15- 45oC as controlled by an external unit that contains a heater/cooler, electronics and power source. We will demonstrate that a minimally invasive tip can block intercostal pain and accurately hold the nerve at 15oC and 45oC while maintaining surrounding tissue in a range of 35-39oC. In Aim #2, we will evaluate efficacy and preliminary safety in 6 conscious sheep for up to 21 days of continuous nerve block as suggested by FDA. Post-therapy we will monitor nerve function recovery and neuropathology will be done at 7- and 90-days post treatment. Successful completion of Phase I will support development of a human-use device and CRO-led pre-clinical GLP safety and efficacy study in Phase II, which in turn will prepare us for an IDE meeting with FDA.